Treating androgen deprivation therapy induced hot flashes and bone loss in men using cis-clomiphene

ABSTRACT

This invention provides: 1) a method of treating androgen-deprivation induced osteoporosis, bone fractures, loss of bone mineral density (BMD), and/or hot flashes in a male subject suffering from prostate cancer; 2) a method of preventing androgen-deprivation induced osteoporosis, bone fractures, loss of bone mineral density (BMD), and/or hot flashes in a male subject suffering from prostate cancer; 3) a method of suppressing or inhibiting androgen-deprivation induced osteoporosis, bone fractures, loss of bone mineral density (BMD), and/ or hot flashes in a male subject suffering from prostate cancer; and 4) a method of reducing the risk of developing androgen-deprivation induced osteoporosis, bone fractures, loss of bone mineral density (BMD), and/ or hot flashes in a male subject suffering from prostate cancer, by administering to the subject a pharmaceutical composition comprising cis-clomiphene or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

This application is a continuation of U.S. application Ser. No.15/879,861, filed Jan. 25, 2018, now allowed; which is a division ofU.S. application Ser. No. 15/327,726, filed Jan. 20, 2017, now U.S. Pat.No. 9,913,815; which is a 371 of International Patent Application No.PCT/US15/41761, filed Jul. 23, 2015, which claims priority benefit ofU.S. Provisional Application No. 62/028,540, filed Jul. 24, 2014, thedisclosures of which patent applications are incorporated herein byreference.

1. Field of the Invention

This invention relates to the prevention and treatment ofandrogen-deprivation induced osteoporosis, bone fractures and/or loss ofbone mineral density (BMD) and hot flashes in men suffering fromprostate cancer. More particularly, this invention relates to a methodof treating, preventing, suppressing, inhibiting, or reducing the riskof developing androgen-deprivation induced osteoporosis, bone fracturesand/or loss of BMD and hot flashes in men suffering from prostatecancer, comprising administering to a male subject suffering fromprostate cancer cis-clomiphene or a pharmaceutically acceptable saltthereof.

2. Description of Related Art

Prostate cancer is one of the most frequently diagnosed noncutaneouscancers among men in the United States. One of the approaches to thetreatment of prostate cancer is by androgen deprivation therapy (ADT).The male sex hormone, testosterone, stimulates the growth of cancerousprostatic cells and, therefore, is the primary fuel for the growth ofprostate cancer. The goal of androgen deprivation is to decrease thestimulation by testosterone of the cancerous prostatic cells.Testosterone normally is produced by the testes in response tostimulation from a hormonal signal called luteinizing hormone (LH) whichin turn is stimulated by luteinizing-hormone releasing hormone (LHRH).Androgen deprivation therapy is accomplished either surgically bybilateral orchiectomy or chemically by LHRH agonists or antagonists withor without nonsteroidal antiandrogens, like bicalutamide orenzalutamide, or lyase inhibitors like abiraterone.

Current studies suggest that early ADT in patients with micrometastaticdisease may indeed prolong survival [Messing E M, et al (1999), N Engl JMed 34, 1781-1788; Newling (2001), Urology 58(Suppl 2A), 50-55].Moreover, ADT is being employed in numerous new clinical settings,including neoadjuvant therapy prior to radical prostatectomy, long-termadjuvant therapy for patients at high risk for recurrence followingradiation or surgery, neoadjuvant therapy for radiation, and treatmentof biochemical recurrence following radiation or surgery [Carroll, et al(2001), Urology 58, 14; Horwitz E M, et al (2001), Int J Radiat OncolBiol Phy March 15; 49(4), 947-56]. Thus, more prostate cancer patientshave become candidates for and are being treated by ADT. Moreover, theseprostate cancer patients are undergoing ADT earlier and longer than inthe past, which in some cases may be as long as 10 or more years.

Unfortunately, ADT has significant adverse side effects, like hotflashes, osteoporosis, decreased lean muscle mass, depression and othermood changes, loss of libido, and erectile dysfunction [Stege R (2000),Prostate Suppl 10, 38-42]. Consequently, complications of ADT nowcontribute significantly to the morbidity, and in some cases themortality, of men suffering from prostate cancer.

Hot flashes are characterized by the subjective sensation of a rise intemperature in the face and trunk and are accompanied by cutaneousvasodilatation predominantly in the face, throat and extremities,usually followed by profuse sweating. Following the administration ofLHRH agonists or antagonists, the steep decline in serum luteinizinghormone and follicle stimulating hormone and rapid and sustainedreductions in testosterone and estrogen blood levels results in therelease of hypothalamic catecholamines, in particular norepinephrine.These flood the thermoregulation center in the upper hypothalamus,resulting in abnormal and poorly regulated peripheral vasodilatation andthe occurrence of hot flushes and perspiration. (Khan et al. 2014,Trends Urol. Men's Health 5(1), 31-33).

It is estimated that up to 80 per cent of patients on ADT willexperience hot flashes and up to 27 per cent of patients report them astheir most troublesome side effect. Most patients will continue toexperience these symptoms for as long as they are receiving ADT. Hotflashes can significantly impact on a patient's quality of life. Giventhat exposure to ADT may be lifelong in the palliative setting and maybe two to three years in the adjuvant setting, there is a need toaddress all associated side effects and deal with them effectively inorder to improve compliance with treatment and quality of life.(Reviewed in Khan 2014).

It is well established that the bone mineral density (BMD) of malesdecreases with age. Decreased amounts of bone mineral content anddensity correlates with decreased bone strength and predispose tofracture. The molecular mechanisms underlying the pleiotropic effects ofsex-hormones in non-reproductive tissues are only beginning to beunderstood, but it is clear that physiologic concentrations of androgensand estrogens play an important role in maintaining bone homeostasisthroughout the life-cycle. Consequently, when androgen or estrogendeprivation occurs, there is a resultant increase in the rate of boneremodeling that tilts the balance of resorption and formation in thefavor of resorption, contributing to an overall loss of bone mass. Inmales, the natural decline in sex-hormones at maturity (direct declinein androgens as well as lower levels of estrogens derived fromperipheral aromatization of androgens) is associated with the frailty ofbones. Moreover, an important side effect in men suffering from prostatecancer undergoing ADT is the development of bone loss leading toosteoporosis and bone fractures. Loss of BMD occurs in the majority ofpatients being treated by ADT by 6 months.

New innovative approaches are urgently needed at both the basic scienceand clinical levels to decrease the incidence of androgen-deprivationinduced hot flashes and bone loss and fractures in men suffering fromprostate cancer on ADT.

SUMMARY OF THE INVENTION

In one embodiment, this invention provides a method of treating asubject suffering from a disorder selected from the group consisting ofosteoporosis, bone fractures, loss of bone mineral density (BMD) and hotflashes, the method comprising the step of administering to said subjectan effective amount therefor of a pharmaceutical composition comprisingcis-clomiphene or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention provides a method of treating asubject with hot flashes, the method comprising the step ofadministering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof.

In one embodiment, this invention provides a method of preventing hotflashes in a subject, the method comprising the step of administering tothe subject cis-clomiphene or a pharmaceutically acceptable saltthereof.

In one embodiment, this invention provides a method of suppressing orinhibiting hot flashes in a subject, the method comprising the step ofadministering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof.

In one embodiment, this invention provides a method of reducing the riskof developing hot flashes in a subject, the method comprising the stepof administering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the cis-clomiphene and/or the pharmaceuticallyacceptable salt thereof is administered at a daily dosage of about 5 mg.In another embodiment, the cis-clomiphene and/or the pharmaceuticallyacceptable salt thereof is administered at a daily dosage of about 15mg. In another embodiment, the cis-clomiphene and/or thepharmaceutically acceptable salt thereof is administered at a dailydosage of about 25 mg. In another embodiment, the cis-clomiphene and/orthe pharmaceutically acceptable salt thereof is administered at a dailydosage of about 50 mg.

The present invention provides a safe and effective method for treating,preventing, suppressing, inhibiting or reducing the risk of developingandrogen-deprivation induced osteoporosis, bone fractures and/or loss ofBMD and hot flashes and is particularly useful for treating malesubjects suffering from prostate cancer having an elevated risk ofdeveloping androgen-deprivation induced osteoporosis, bone fracturesand/or loss of BMD and hot flashes.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides: 1) a method of treating a subject with hotflashes; 2) a method of preventing hot flashes in a subject; 3) a methodof suppressing or inhibiting hot flashes in a subject; 4) a method ofreducing the risk of developing hot flashes in a subject; 5) a method oftreating androgen-deprivation induced osteoporosis in a male subjectsuffering from prostate cancer; 6) a method of preventingandrogen-deprivation induced osteoporosis in a male subject sufferingfrom prostate cancer; 7) a method of suppressing or inhibitingandrogen-deprivation induced osteoporosis in a male subject sufferingfrom prostate cancer; 8) a method of reducing the risk of developingandrogen-deprivation induced osteoporosis in a male subject sufferingfrom prostate cancer; 9) a method of treating androgen-deprivationinduced loss of BMD in a male subject suffering from prostate cancer;10) a method of preventing androgen-deprivation induced loss of BMD in amale subject suffering from prostate cancer; 11) a method of suppressingor inhibiting androgen-deprivation induced loss of BMD in a male subjectsuffering from prostate cancer; 12) a method of reducing the risk ofdeveloping androgen-deprivation induced loss of BMD in a male subjectsuffering from prostate cancer; 13) a method of treatingandrogen-deprivation induced bone fractures in a male subject sufferingfrom prostate cancer; 14) a method of preventing androgen-deprivationinduced bone fractures in a male subject suffering from prostate cancer;15) a method of suppressing or inhibiting androgen-deprivation inducedbone fractures in a male subject suffering from prostate cancer; 16) amethod of reducing the risk of developing androgen-deprivation inducedbone fractures in a male subject suffering from prostate cancer byadministering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof.

Cis-clomiphene has the chemical structure:

Cis-clomiphene is currently marketed as a component of CLOMID®, which isa mixture of two enantiomers, trans-clomiphene and cis-clomiphene, in aratio of trans:cis isomer ranging from about 50:50 to about 70:30.Cis-clomiphene is the more estrogenic isomer of the two. Substantiallypure cis-clomiphene and the pharmaceutically acceptable salts thereofare already well known in the art (see, for example, U.S. Pat. No.3,848,030, incorporated herein by reference) and, moreover, even werethey not well known in the art methods by which they can be prepared arewell known to and within the skill of the ordinary artisan. By“substantially pure” is meant cis-clomiphene containing less than 10% byweight, based on the total weight of the enantiomer mixture oftrans-clomiphene, preferably less than 5%, more preferably less than 2%,most preferably not more than a trace of trans-clomiphene.

One of the important side effects of CLOMID® as listed in the packageinsert is hot flashes. Thus, CLOMID® does not treat hot flashes. Anunexpected finding is that the cis-clomiphene isomer, the estrogenicisomer, can treat and prevent hot flashes and bone loss and fractures.The present methods contemplate the administration of cis-clomiphene ora pharmaceutically acceptable salt thereof.

In another embodiment, the present invention contemplates theadministration of substantially pure clomiphene or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention contemplates theadministration of clomiphene or a pharmaceutically acceptable saltthereof enriched in cis-clomiphene compared to CLOMID®. Thus, in thisembodiment, the present invention contemplates the administration ofclomiphene or a pharmaceutically acceptable salt thereof comprising bothtrans-isomer and cis-isomer in a ratio of trans:cis ranging from 49:51to 0:100, preferably 25:75 to 0:100, most preferably 10:90 to 0:100.

In yet another embodiment, the present invention contemplates theadministration of clomiphene or a pharmaceutically acceptable saltthereof comprising about 100% by weight of cis-clomiphene or apharmaceutically acceptable salt thereof In this context, “about 100% byweight of cis-clomiphene or a pharmaceutically acceptable salt thereof”means the composition administered comprises less than 2% by weight oftrans-isomer, preferably not more than a trace amount of trans-isomer.

Various embodiments of dosage ranges are contemplated by this invention.In one embodiment, the dosage is in the range of 1-80 mg/day. In anotherembodiment, the dosage is in the range of 5-80 mg/day. In anotherembodiment the dosage is in the range of 35-66 mg/day. In anotherembodiment the dosage is in the range of 20-80 mg/day. In anotherembodiment the dosage is in the range of 20-60 mg/day. In anotherembodiment the dosage is in the range of 40-60 mg/day. In anotherembodiment the dosage is in a range of 45-60 mg/day. In anotherembodiment the dosage is in the range of 15-25 mg/day. In anotherembodiment the dosage is in the range of 55-65 mg/day. In oneembodiment, the dosage is 5 mg/day. In another embodiment, the dosage is15 mg/day. In another embodiment, the dosage is 25 mg/day. In anotherembodiment, the dosage is 50 mg/day.

Accordingly, in one embodiment, this invention provides a method oftreating a subject with hot flashes, the method comprising the step ofadministering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof, at a dosage of about 5 mg to about 50 mg perday.

In one embodiment, this invention provides a method of preventing hotflashes in a subject, the method comprising the step of administering tothe subject cis-clomiphene or a pharmaceutically acceptable saltthereof, at a dosage of about 5 mg to about 50 mg per day.

In one embodiment, this invention provides a method of suppressing orinhibiting hot flashes in a subject, the method comprising the step ofadministering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof, at a dosage of about 5 mg to about 50 mg perday.

In one embodiment, this invention provides a method of reducing the riskof developing hot flashes in a subject, the method comprising the stepof administering to the subject cis-clomiphene or a pharmaceuticallyacceptable salt thereof, at a dosage of about 5 mg to about 50 mg perday.

In one embodiment, the cis-clomiphene or the pharmaceutically acceptablesalt thereof is administered at a daily dosage of about 5 mg. In anotherembodiment, the cis-clomiphene or the pharmaceutically acceptable saltthereof is administered at a daily dosage of about 15 mg. In anotherembodiment, the cis-clomiphene or the pharmaceutically acceptable saltthereof is administered at a daily dosage of about 25 mg. In anotherembodiment, the cis-clomiphene or the pharmaceutically acceptable saltthereof is administered at a daily dosage of about 50 mg.

Hot flashes are caused by thermoregulatory dysfunction because of thelow levels of testosterone and estrogen induced by ADT and is manifestedby varying frequencies of sweating and chills that can be mild to severein intensity. Moderate to severe hot flashes may cause the subject tonot be able to continue normal daily activities. Hot flashes are one ofthe major reasons why patients become noncompliant with theiranticancer, androgen deprivation therapy. Osteoporosis is a systemicskeletal disease, characterized by low bone mass and deterioration ofbone tissue, with a consequent increase in bone fragility andsusceptibility to fracture. In osteoporotic patients, bone strength isabnormal, with a resulting increase in the risk of fracture.Osteoporosis depletes both the calcium and the protein collagen normallyfound in the bone, resulting in either abnormal bone quality ordecreased bone density. Bones that are affected by osteoporosis canfracture with only a minor fall or injury that normally would not causea bone fracture. The fracture can be either in the form of cracking (asin a hip fracture) or collapsing (as in a compression fracture of thespine). The spine, hips, and wrists are common areas of osteoporosisbone fractures, although fractures can also occur in other skeletalareas.

Bone mineral density is a measured calculation of the true mass of bone.The absolute amount of bone as measured by BMD generally correlates withbone strength and its ability to bear weight. By measuring BMD, it ispossible to predict fracture risk in the same manner that measuringblood pressure can help predict the risk of stroke.

Bone mineral density in one embodiment can be measured by knownbone-mineral content mapping techniques. Bone density of the hip, spine,wrist, or calcaneus may be measured by a variety of techniques. Thepreferred method of BMD measurement is dual-energy x-ray densitometry(DXA). Bone mineral density of the hip, antero-posterior spine, lateralspine, and wrist can be measured using this technology. Measurement atany site predicts overall risk of fracture, but information from aspecific site is the best predictor of fracture at that site.Quantitative computerized tomography is also used to measure BMD of thespine. See for example, “Nuclear Medicine: “Quantitative Procedures”, byWahner H W, Dunn W L, Thorsen H C, et al, published by Toronto Little,Brown & Co., 1983, (see pages 107-132). An article entitled “Assessmentof Bone Mineral Part 1” appeared in the Journal of Nuclear Medicine, pp1134-1141, (1984). Another article entitled “Bone Mineral Density of TheRadius” appeared in Vol. 26, No. 11, (1985) Nov. Journal of NuclearMedicine at pp 13-39. Abstracts on the use of gamma cameras forbone-mineral content measurements are (a) S. Hoory et al, Radiology,Vol. 157(P), p. 87 (1985), and (b) C. R. Wilson et al, Radiology, Vol.157(P), p. 88 (1985).

The present invention provides a safe and effective method for treating,preventing, suppressing, inhibiting or reducing the risk of developingandrogen-deprivation induced osteoporosis and/or loss of BMD and isparticularly useful for treating male subjects suffering from prostatecancer having an elevated moderate to severe hot flashes induced by riskof developing androgen-deprivation induced osteoporosis. In oneembodiment, the male subject is a mammalian subject. In anotherembodiment, the male subject is a human subject.

Furthermore, the anti-estrogens presented herein cis-clomiphene and thepharmaceutically acceptable salts thereof are effective at treating,suppressing or inhibiting osteopenia accompanied by bone loss.“Osteopenia” refers to decreased calcification or density of bone. Thisis a term which encompasses all skeletal systems in which such acondition is noted.

As contemplated herein, the present invention relates to the use ofcis-clomiphene or a pharmaceutically acceptable salt thereof fortreating, preventing, suppressing, inhibiting or reducing the risk ofdeveloping androgen-deprivation induced osteoporosis and/or loss of BMDat a dosage of about 5 mg to about 50 mg per day. Thus, in oneembodiment, the methods of the present invention comprise administeringcis-clomiphene. In another embodiment, the methods of the presentinvention comprise administering a pharmaceutically acceptable salt ofthe cis-clomiphene.

The invention includes “pharmaceutically acceptable salts” of theamino-substituted compound with organic and inorganic acids, forexample, citric acid and hydrochloric acid. The invention also includesN-oxides of the amino substituent.

Pharmaceutical Compositions

In one embodiment, the methods of the present invention compriseadministering a pharmaceutical composition comprising the cis-clomipheneor a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier. The pharmaceutical composition is administered to amale subject suffering from prostate cancer; for treating and/orpreventing androgen-deprivation induced osteoporosis and/or loss of BMD;for suppressing or inhibiting androgen-deprivation induced osteoporosisand/or loss of BMD; and/or for reducing the risk of developingandrogen-deprivation induced osteoporosis and/or loss of BMD in the malesubject.

As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the cis-clomipheneand/or pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier or diluent. A “therapeuticallyeffective amount” as used herein refers to that amount which provides atherapeutic effect for a given condition and administration regimen.

The pharmaceutical compositions containing the cis-clomiphene or apharmaceutically acceptable salt thereof can be administered to asubject by any method known to a person skilled in the art, such asparenterally, paracancerally, transmucosally, transdermally,intramuscularly, intravenously, intradermally, subcutaneously,intraperitonealy, intraventricularly, intracranially, intravaginally orintratumorally.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pelletsand the like. Suitable liquid oral formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment of the present invention, the cis-clomiphene and/orpharmaceutically acceptable salt thereof are formulated in a capsule. Inaccordance with this embodiment, the compositions of the presentinvention comprise, in addition to the cis-clomiphene and/orpharmaceutically acceptable salt thereof active compound and the inertcarrier or diluent, a hard gelating capsule.

Further, in another embodiment, the pharmaceutical compositions areadministered by intravenous, intraarterial, intranasal, or intramuscularinjection of a liquid preparation. Suitable liquid formulations includesolutions, suspensions, dispersions, emulsions, oils and the like. Inone embodiment, the pharmaceutical compositions are administeredintravenously, and are thus formulated in a form suitable forintravenous administration. In another embodiment, the pharmaceuticalcompositions are administered intraarterially, and are thus formulatedin a form suitable for intraarterial administration. In anotherembodiment, the pharmaceutical compositions are administeredintramuscularly, and are thus formulated in a form suitable forintramuscular administration.

Further, in another embodiment, the pharmaceutical compositions areadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration.

Suitable topical formulations include gels, ointments, creams, lotions,drops and the like. For topical administration, the cis-clomipheneand/or pharmaceutically acceptable salt thereof are prepared and appliedas solutions, suspensions, or emulsions in a physiologically acceptablediluent with or without a pharmaceutical carrier.

Further, in another embodiment, the pharmaceutical compositions areadministered as a suppository, for example a rectal suppository or aurethral suppository. Further, in another embodiment, the pharmaceuticalcompositions are administered by subcutaneous implantation of a pellet.In a further embodiment, the pellet provides for controlled release ofcis-clomiphene or pharmaceutically acceptable salt thereof over a periodof time.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial, orintramuscular injection) include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Examples are sterile liquids such as water and oils, with orwithout the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. In general, water, saline, aqueous dextrose andrelated sugar solutions, and glycols such as propylene glycols orpolyethylene glycol are preferred liquid carriers, particularly forinjectable solutions. Examples of oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,mineral oil, olive oil, sunflower oil, and fish-liver oil.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., glycerol, polyethyleneglycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite,butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose,hydroxypropylmethyl cellulose), viscosity increasing agents (e.g.carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweeteners (e.g. aspartame, citric acid), preservatives (e.g.,Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid,magnesium stearate, polyethylene glycol, sodium lauryl sulfate),flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethylphthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropylcellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates) and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled-release compositions, i.e. compositions in which thecis-clomiphene and/or the pharmaceutically acceptable salt thereof isreleased over a period of time after administration. Controlled- orsustained-release compositions include formulation in lipophilic depots(e.g. fatty acids, waxes, oils). In another embodiment, the compositionis an immediate-release composition, i.e. a composition in which all ofthe cis-clomiphene or pharmaceutically acceptable salt thereof isreleased immediately after administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980);Saudek et al., N. Engl. J. Med. 321: 574 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984). Other controlled-release systems arediscussed in the review by Langer (Science 249:1527-1533 (1990).

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts.) Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

Also comprehended by the invention are particulate compositions coatedwith polymers (e.g. poloxamers or poloxamines) and the compound coupledto antibodies directed against tissue-specific receptors, ligands orantigens or coupled to ligands of tissue-specific receptors.

Also comprehended by the invention are compounds modified by thecovalent attachment of water-soluble polymers such as polyethyleneglycol, copolymers of polyethylene glycol and polypropylene glycol,carboxymethyl cellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone or polyproline. The modified compounds are known toexhibit substantially longer half-lives in blood following intravenousinjection than do the corresponding unmodified compounds (Abuchowski etal., 1981; Newmark et al., 1982; and Katre et al., 1987). Suchmodifications may also increase the compound's solubility in aqueoussolution, eliminate aggregation, enhance the physical and chemicalstability of the compound, and greatly reduce the immunogenicity andreactivity of the compound. As a result, the desired in vivo biologicalactivity may be achieved by the administration of such polymer-compoundabducts less frequently or in lower doses than with the unmodifiedcompound.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the cis-clomiphene and/or pharmaceutically acceptablesalt thereof are mixed with additives customary for this purpose, suchas vehicles, stabilizers, or inert diluents, and converted by customarymethods into suitable forms for administration, such as tablets, coatedtablets, hard or soft gelatin capsules, aqueous, alcoholic or oilysolutions. For parenteral administration, the cis-clomiphene and/orpharmaceutically acceptable salt thereof are converted into a solution,suspension, or emulsion, if desired with the substances customary andsuitable for this purpose, for example, solubilizers or other.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the aminogroup of the molecule), which are formed with inorganic acids such as,for example, hydrochloric or phosphoric acids, or such organic acids asacetic, oxalic, tartaric, mandelic, and the like.

For use in medicine, the salts of the cis-clomiphene arepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid.

In another embodiment, the term “contacting” means that thecis-clomiphene and/or pharmaceutically acceptable salt thereof of thepresent invention is introduced into a subject receiving treatment, andthe cis-clomiphene and/or pharmaceutically acceptable salt thereof isallowed to come in contact with the androgen receptor in vivo.

As used herein, the term “treating” includes preventative as well asdisorder remitative treatment. As used herein, the terms “reducing”,“suppressing” and “inhibiting” have their commonly understood meaning oflessening or decreasing. As used herein, the term “progression” meansincreasing in scope or severity, advancing, growing or becoming worse.As used herein, the term “recurrence” means the return of a diseaseafter a remission.

As used herein, the term “administering” refers to bringing a subject incontact with the cis-clomiphene and/or pharmaceutically acceptable saltthereof of the present invention. As used herein, administration can beaccomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells ortissues of living organisms, for example humans. In one embodiment, thepresent invention encompasses administering the compounds of the presentinvention to a subject.

In one embodiment, the methods of the present invention compriseadministering the cis-clomiphene and/or pharmaceutically acceptable saltthereof as the sole active ingredient. However, also encompassed withinthe scope of the present invention are methods for hormone therapy, fortreating prostate cancer, for delaying the progression of prostatecancer, and for preventing and/or treating the recurrence of prostatecancer, which comprise administering the cis-clomiphene and/orpharmaceutically acceptable salt thereof in combination with one or moretherapeutic agents. These agents include, but are not limited to: LHRHagonists, LHRH antagonists, reversible antiandrogens (such asbicalutamide, flutamide, enzalutamide, and ARN-509), lyase inhibitors(abiraterone), other anti-estrogens, anticancer drugs, 5-alpha reductaseinhibitors, aromatase inhibitors, progestins, selective androgenreceptor modulators (SARMS) or agents acting through other nuclearhormone receptors.

Thus, in one embodiment, the methods of the present invention includeusing compositions and pharmaceutical compositions comprisingcis-clomiphene and/or pharmaceutically acceptable salt thereof incombination with an LHRH agonist or antagonist. In another embodiment,the methods of the present invention include using compositions andpharmaceutical compositions comprising cis-clomiphene and/orpharmaceutically acceptable salt thereof in combination with areversible antiandrogen. In another embodiment, the methods of thepresent invention include using compositions and pharmaceuticalcompositions comprising cis-clomiphene and/or pharmaceuticallyacceptable salt thereof in combination with an anti-estrogen. In anotherembodiment, the methods of the present invention include usingcompositions and pharmaceutical compositions comprising cis-clomipheneand/or pharmaceutically acceptable salt thereof in combination with ananticancer drug. In another embodiment, the methods of the presentinvention include using compositions and pharmaceutical compositionscomprising cis-clomiphene and/or pharmaceutically acceptable saltthereof in combination with a 5-alpha reductase inhibitor. In anotherembodiment, the methods of the present invention include usingcompositions and pharmaceutical compositions comprising cis-clomipheneand/or pharmaceutically acceptable salt thereof in combination with anaromatase inhibitor. In another embodiment, the methods of the presentinvention include using compositions and pharmaceutical compositionscomprising cis-clomiphene and/or pharmaceutically acceptable saltthereof in combination with a progestin. In another embodiment, themethods of the present invention include using compositions andpharmaceutical compositions comprising cis-clomiphene and/orpharmaceutically acceptable salt thereof in combination with a SARM. Inanother embodiment, the methods of the present invention include usingcompositions and pharmaceutical compositions comprising cis-clomipheneand/or pharmaceutically acceptable salt thereof in combination with anagent acting through other nuclear hormone receptors.

A pharmaceutically effective dosage of the cis-clomiphene orpharmaceutically acceptable salt thereof is administered to the patientsfor an effective time period, preferably, for 2 years and mostpreferably continuously (for the remainder of the patient's life). Forexample, at a daily dose of 5-10 mg once or twice a day, cis-clomipheneor pharmaceutically acceptable salt thereof is administered to obtain atarget reduction in the frequency of hot flashes and can thus give anindication of whether dose adjustment should be undertaken.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Treatment of Hot Flashes

Due to the deleterious effects of testosterone on prostate cancer, thegold standard treatment for advanced prostate cancer is surgical orchemical castration of the patient. However, the resulting lowtestosterone and estrogen levels can have significant side effectsincluding loss of bone leading to osteoporosis, and fractures as well ashot flashes. The adverse effect of hot flashes is primarily a quality oflife issue. However, hot flashes are often cited as the number onereason for the lack of compliance with anticancer therapy including ADTin these men.

Men suffering from hot flashes who have advanced prostate cancer on ADTare given daily doses of 25 mg of cis-clomiphene citrate (about 100%cis-isomer) for a period of at least three months. Assessments are madeas to the frequency and severity of hot flashes at baseline and afterthree months of treatment.

Example 2 Effect of Cis-Clomiphene on Bone Turnover

Men who have advance prostate cancer on ADT are treated with 50 mg/d ofsubstantially cis-clomiphene for 6 months. At Day 180, baseline boneturnover markers like serum bone specific alkaline phosphatase and arecompared to current values as well as BMD by DEXA. The expectation isthat cis-clomiphene shows estrogenic effects on bone favorably affectingbone turnover markers and BMD in men.

Bone analysis methodology may be carried out as described in U.S. PatentPublication No. 2004/0214898, the pertinent contents of which areincorporated herein by reference.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims which follow:

What is claimed is:
 1. A method of treating a subject suffering from adisorder selected from the group consisting of osteoporosis, bonefractures, loss of bone mineral density (BMD) and hot flashes, saidmethod comprising the step of administering to said subject an effectiveamount therefor of a pharmaceutical composition comprisingcis-clomiphene or a pharmaceutically acceptable salt thereof.
 2. Themethod according to claim 1, wherein said administering comprisesintravenously, intraarterially, intranasal spray, or intramuscularlyinjecting to said subject said pharmaceutical composition in liquidform; subcutaneously implanting in said subject a pellet containing saidpharmaceutical composition; orally administering to said subject saidpharmaceutical composition in a liquid or solid form; or topicallyapplying to the skin surface of said subject said pharmaceuticalcomposition.
 3. The method according to claim 2, wherein saidpharmaceutical composition is a pellet, a tablet, a capsule, a solution,a suspension, an emulsion, an elixir, a gel, a cream, a suppository or aparenteral formulation.
 4. The method according to claim 1, wherein saidcis-clomiphene or pharmaceutically acceptable salt thereof isadministered at a dosage of about 5 mg per day.
 5. The method accordingto claim 1, wherein said cis-clomiphene or pharmaceutically acceptablesalt thereof is administered at a dosage of about 15 mg per day.
 6. Themethod according to claim 1, wherein said cis-clomiphene orpharmaceutically acceptable salt thereof is administered at a dosage ofabout 25 mg per day.
 7. The method according to claim 1, wherein saidcis-clomiphene or pharmaceutically acceptable salt thereof isadministered at a dosage of 50 mg per day.
 8. The method according toclaim 1, wherein the disorder is osteoporosis.
 9. The method accordingto claim 1, wherein the disorder is bone fractures.
 10. The methodaccording to claim 1, wherein the disorder is loss of bone mineraldensity.
 11. The method according to claim 1, wherein the disorder ishot flashes.
 12. A method of suppressing, inhibiting or reducing therisk of a disorder to a subject undergoing androgen-deprivation therapy,said disorder being selected from the group consisting of osteoporosis,bone fractures, loss of bone mineral density (BMD) and hot flashes, saidmethod comprising the step of administering to said subject an effectiveamount therefor of a pharmaceutical composition comprisingcis-clomiphene or a pharmaceutically acceptable salt thereof.
 13. Themethod according to claim 12, wherein said administering comprisesintravenously, intraarterially, intranasal spray, or intramuscularlyinjecting to said subject said pharmaceutical composition in liquidform; subcutaneously implanting in said subject a pellet containing saidpharmaceutical composition; orally administering to said subject saidpharmaceutical composition in a liquid or solid form; or topicallyapplying to the skin surface of said subject said pharmaceuticalcomposition.
 14. The method according to claim 12, wherein saidpharmaceutical composition is a pellet, a tablet, a capsule, a solution,a suspension, an emulsion, an elixir, a gel, a cream, a suppository or aparenteral formulation.
 15. The method according to claim 12, whereinsaid cis-clomiphene or pharmaceutically acceptable salt thereof isadministered at a dosage of about 5 mg per day.
 16. The method accordingto claim 12, wherein said cis-clomiphene or pharmaceutically acceptablesalt thereof is administered at a dosage of about 15 mg per day.
 17. Themethod according to claim 12, wherein said cis-clomiphene orpharmaceutically acceptable salt thereof is administered at a dosage ofabout 25 mg per day.
 18. The method according to claim 12, wherein saidcis-clomiphene or pharmaceutically acceptable salt thereof isadministered at a dosage of 50 mg per day.
 19. The method according toclaim 12, wherein the disorder is osteoporosis.
 20. The method accordingto claim 12, wherein the disorder is bone fractures.
 21. The methodaccording to claim 12, wherein the disorder is loss of bone mineraldensity.
 22. The method according to claim 12, wherein the disorder ishot flashes.